EP0094159B1 - Dihydropyridinderivate, deren Herstellung und Verwendung - Google Patents

Dihydropyridinderivate, deren Herstellung und Verwendung Download PDF

Info

Publication number
EP0094159B1
EP0094159B1 EP83302139A EP83302139A EP0094159B1 EP 0094159 B1 EP0094159 B1 EP 0094159B1 EP 83302139 A EP83302139 A EP 83302139A EP 83302139 A EP83302139 A EP 83302139A EP 0094159 B1 EP0094159 B1 EP 0094159B1
Authority
EP
European Patent Office
Prior art keywords
dihydropyridine
alkyl
piperazinyl
cycloalkyl
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP83302139A
Other languages
English (en)
French (fr)
Other versions
EP0094159A1 (de
Inventor
Kanji Meguro
Akinobu Nagaoka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
Original Assignee
Takeda Chemical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/JP1982/000159 external-priority patent/WO1983004023A1/ja
Priority claimed from PCT/JP1983/000008 external-priority patent/WO1984002702A1/ja
Application filed by Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Priority to AT83302139T priority Critical patent/ATE50987T1/de
Publication of EP0094159A1 publication Critical patent/EP0094159A1/de
Priority to MYPI87002229A priority patent/MY102082A/en
Application granted granted Critical
Publication of EP0094159B1 publication Critical patent/EP0094159B1/de
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the alkyls designated by R', R 2 and R 3 are (C 1-6 ) alkyls which may be either straight-chain or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, although C 1 - 4 alkyls are particularly desirable.
  • These alkyls may each terminate with a (C 3 - 6 ) cycloalkyl group (e.g. cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl).
  • the cycloalkyl is (C 3 -C 6 ) cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • the alkoxyalkyl ' has a total of 3 to 7 carbon atoms and may for example be methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, or 2-ethoxy-1-methylethyl.
  • R 4 and R 5 may be the same or different, and be present in any optional position of the ring, although they are preferably located in the 2- or/and 3-position with respect to the site of attachment to the dihydropyridine ring.
  • the halogen as an example of such substituents may be fluorine, chlorine, bromine or iodine and is preferably fluorine or chlorine.
  • the alkyl and cycloalkyl are those mentioned for R 1 to R 3 .
  • the alkoxy and alkylthio are derived from or contain (C 1 - 3 ) alkyls, thus being exemplified by methoxy, ethoxy, propoxy and isopropoxy and by methylthio, ethylthio, propylthio and isopropylthio, respectively.
  • the alkoxycarbonyl contains 2 to 4 carbon atoms, such as methoxycarbonyl or ethoxycarbonyl.
  • the alkyl and cycloalkyl, as designated by R 6 are those mentioned for R 1 to R 3 .
  • the phenyl C 1-3 alkyl is, e.g., benzyl, a-phenylethyl, ⁇ -phenylethyl or y-phenylpropyl, and the phenyl or naphthyl may have the same or different substituents R 4 and R 5 in optional positions.
  • the pyridyl may be 2-pyridyl, 3-pyridyl or 4-pyridyl, which may have the substituents mentioned for R 4 and R 5 .
  • the C 2 - 4 alkylene designated by A may be straight-chain or branched, thus being exemplified by ethylene, trimethylene, propylene, tetramethylene or 1,2-dimethylethylene.
  • aryl and pyridyl designated by Ar are those mentioned for R and may have substituents similar to those mentioned.
  • Ar may represent either the same aryl or pyridyl or a different aryl or pyridyl group.
  • n which is an integer of 0 to 2
  • n which is an integer of 0 to 2
  • the case in which n is 0 is that the nitrogen atom is directly attached to Ar.
  • X is oxygen or sulfur
  • the ring is furan or thiophene
  • the ring is pyridine
  • heterocyclic rings or fused heterocyclic rings may be attached in any optional position thereof to the 4-position of the dihydropyridine ring but the cases in which X is adjacent to the site of attachment to the dihydropyridine ring are particularly desirable.
  • Preferred examples of such heterocyclic or fused heterocyclic groups are 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 2,1,3-benzoxadiazol-4-yl, and 2,1,3-benzothiadiazol-4-yl.
  • the starting material corresponding to a fragment which can constitute the dihydropyridine derivative (I) may be subjected to a dehydration and cyclization reaction with the remaining fragment(s) according to one of the following production processes (A) to (F); (In the above formulas, all symbols have the same meanings as defined hereinbefore).
  • acetone, methyl ethyl ketone, N,N-dimethylformamide, etc. may also be employed as well as those mentioned above, and the reaction may also be conducted at 20°C to 100°C.
  • the halogen Y in formula (IX) is chlorine, bromine or iodine, and when Y is chlorine or bromine, the reaction may be carried out in the presence of about 0.1 to 1 molar equivalents of sodium iodide, potassium iodide or the like per mole of (VII) so as to accelerate the reaction.
  • the starting compound (VI) can be synthesized by permitting ammonia to react with the starting compound (IV) used in Production Process A.
  • a suitable solvent e.g. methanol, ethanol, ethyl ether, dioxane, tetrahydrofuran
  • an excess of ammonia gas is bubbled into the reaction mixture at about 0°C to about 60°C.
  • a solution of ammonia in the above-mentioned solvent is added and the reaction is conducted in a closed vessel at about 0°C to about 60°C. In either manner, (VI) can be easily synthesized.
  • benzylidene ⁇ -keto ester (VII) is reacted with compound (VI) to give the object compound (I).
  • the reaction conditions of this process are also substantially identical with those of Production Process A.
  • each mole of compound (VII) is reacted with 0.8 to 1.5 moles of (VI).
  • the starting benzylidene (3-keto ester (VII) is either a known compound or can be prepared from the aldehyde (III) and ⁇ -keto ester (V) by the conventional procedure [e.g. Organic Reactions 15, 204-599 (1967)].
  • the novel dihydropyridine derivative (I) produced in the manners described above can be isolated in a desired purity by the per se conventional separation and purification procedures such as concentration, extraction, chromatography, reprecipitation, recrystallization, etc. Since (I) contains a basic group, it can be converted to an acid addition salt by the known procedure.
  • the salt is preferably a pharmaceutically acceptable non-toxic salt such as salts with mineral acids (hydrochloride, hydrobromide, phosphate, sulfate, etc.) and salts with organic acids (acetate, succinate, maleate, fumarate, malate, tartarate, methanesulfonate, etc.).
  • the compound (I) and its salt according to this invention have low toxicity and display strong and long-lasting antihypertensive, peripheral vasodilating, coronary artery dilating, cerebral vasodilating, renal vasodilating and other activities in mammalian animals (e.g. mouse, rat, rabbit, dog, cat, man), and are of value in the prevention and treatment of cardiovascular diseases such as hypertension, ischemic heart disease (angina pectoris, myocardial infarction, etc.), cerebral and peripheral circulatory disorder (cerebral infarction, transient cerebral ischemic attack, renal artery stenosis, etc.), for instance.
  • cardiovascular diseases such as hypertension, ischemic heart disease (angina pectoris, myocardial infarction, etc.), cerebral and peripheral circulatory disorder (cerebral infarction, transient cerebral ischemic attack, renal artery stenosis, etc.), for instance.
  • the present compound is very useful in that it is superior to the known dihydropyridine derivatives (e.g. nifedipine, nicardipine) in the intensity and duration of action and has the distinct property of dilating the renal blood vessels to increase the renal blood flow which is not found in the known compounds.
  • the compound of this invention produces a stable antihypertensive effect in a less frequent administration regimen (e.g. 1 to 2 doses per day).
  • the increase of renal blood flow due to its renal vessel dilating activity promotes excretion of excess sodium and suppresses retention of sodium in the body.
  • the retention of sodium in the body due to an excessive intake of sodium chloride and the depressed sodium excreting function in hypertensive patients are improved, leading to an excellent antihypertensive effect.
  • excessive sodium chloride intakes not only cause hypertension but also provoke onset of cerebral apoplexy
  • a mild diuretic action via an increase of renal blood flow appears to be useful for the prevention of hypertensive vascular disorders such as cerebral apoplexy.
  • renin an enzyme which produces angiotensin which is a vasopressor substance
  • the renal hemodynamics improving action of the compounds of this invention may be presumed to supress secretion of renin and the compound (I) and salt thereof are of use as antihypertensive drugs.
  • the compound (I) or its salt it can be administered orally or otherwise in such dosage forms as powders, granules, tablets, capsules, injections, etc. which may be prepared by mixing the compound (1) or salt thereof with a pharmaceutically acceptable carrier, excipient or diluent.
  • the dosage should vary with such factors as the route of administration, the condition, body weight and age of the patient, etc. but for oral administration to an adult patient with hypertension, for instance, 0.05 to 20 mg/kg body weight/day or preferably 0.1 to 4 mg/kg body weight/day is administered divided into 1 to several times a day.
  • test compound was suspended in a 5% solution of gum arabic and orally administered. The dosage was 10 mg/kg for all compounds. Animals in a control group was given the above solution of gum arabic only. Blood pressure measurements were made 1,5,8 and 24 hours after administration of each test compound.
  • Example 2 The monohydrate obtained in Example 1 was dissolved in methanol and the solution was concentrated. Recrystallization from ethyl acetate gave anhydrous 2-(4-benzhydryl-1-piperazinyl)ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride. m.p. 174-180°C [204-206.5°C (decomp.) when measured in a capillary tube].
  • Example 9 The free base obtained in Example 9 was dissolved in a small amount of methanol, an excess of hydrogen chloride in methanol was added thereto, and the mixture was concentrated. The residue was recrystallized from ethanol-ethyl ether to give 2-[4-(4,4'-dimethylbenzhydryl)-1-piperazinyl)ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride as light yellow crystals, m.p. 182-183°C.
  • Example 17 The free base obtained in Example 17 was added in a small amount of methanol, an excess of methanolic hydrogen chloride was added thereto, and the mixture was concentrated. The resulting crystalline precipitate was collected by filtration and recrystallized from methanol to give 2-[4-(3-chlorophenyl)-1-piperazinyl]ethyl methyl 2,6-dimethyl-4-13-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride as yellow crystals, m.p. 192-196°C.
  • the whole amounts of (1) and (2) are mixed with 17 g of corn starch (3) and the mixture is granulated with a paste prepared from 7 g of corn starch (3). Then 5 g of corn starch (3) and the whole amount of (4) are added and the whole mixture is compression molded on a compression tableting machine to give 1000 tablets 7 mm in diameter and each containing 5 mg of (1).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Claims (21)

1. Dihydropyridin-Derivat der Formel (I)
Figure imgb0172
(in der R1, R2 und R3 gleich oder verschieden sind und jeweils C1-6-Alkyl, C3-6-Cycloalkyl-C1-6-alkyl, C3-6-Cycloalkyl oder C3-7-Alkoxyalkyl sind; R4 und R5 gleich oder verschieden sind und jeweils Wasserstoff, Halogen, Nitro, Trifluoromethyl, C1-6-Alkyl, C3-6-Cycloalkyl-C1-6-alkyl, C3-6-Cycloalkyl, C1-3-Alkoxy, Cyano, C2-4-Alkoxycarbonyl oder C1-3-Alkylthio sind; R6 Wasserstoff, C1-6-Alkyl, C3-6-Cycloalkyl-C1-6-alkyl, C3-6-Cycloalkyl, Phenyl-C1-3-alkyl, Phenyl oder Naphthyl, das die gleichen oder unterschiedliche Substituenten R4 und R5 in wahlweisen Positionen haben kann, oder Pyridyl ist; X Sauerstoff, Schwefel, Vinylen, Azomethin oder eine Gruppe der Formel
Figure imgb0173
A C2-4-Alkylen ist; Ar Phenyl oder Naphthyl oder ein Pyridyl ist; m eine ganze Zahl von 1 bis 3 ist; n eine ganze Zahl von 0 bis 2 ist) oder ein pharmazeutisch annehmbares Säureadditionssalz desselben.
2. Dihydropyridin-Derivat nach Anspruch 1, worin m 2 ist.
3. Dihydropyridin-Derivat nach Anspruch 1, worin A Ethylen ist.
4. Dihydropyridin-Derivat nach Anspruch 1, worin X Vinylen ist.
5. Dihydropyridin-Derivat nach Anspruch 1, worin X Azo methin ist.
6. Dihydropyridin-Derivat nach Anspruch 1, worin X Sauerstoff ist.
7. Dihydropyridin-Derivat nach Anspruch 1, worin Ar Phenyl ist.
8. Dihydropyridin-Derivat nach Anspruch 1, worin R6 und Ar jeweils eine Phenyl-Gruppe sind, die gegebenenfalls substituiert sein kann, und n 1 ist.
9. Dihydropyridin-Derivat nach Anspruch 1, worin Ar eine Phenyl-Gruppe ist, die gegebenenfalls substituiert sein kann, X Vinylen ist, A Ethylen ist, m 2 ist und n 0 ist.
10. Dihydropyridin-Derivat nach Anspruch 1, worin R6 und Ar jeweils Phenyl ist, X Vinylen ist, A Ethylen ist, m 2 ist und n 1 ist.
11. Dihydropyridin-Derivat nach Anspruch 1, worin Ar eine Phenyl-Gruppe ist, die gegebenenfalls durch ein oder zwei Halogen-Atome substituiert ist, X Vinylen ist, A Ethylen ist, m 2 ist und n 0 ist.
12. Dihydropyridin-Derivat nach Anspruch 1, worin Ar eine Phenyl-Gruppe ist, die gegebenenfalls durch ein oder zwei Chlor-Atome substituiert ist, X Vinylen ist, A Ethylen ist, m 2 ist und n 0 ist.
13. Dihydropyridin-Derivat nach Anspruch 1, das 2-(4-Benzhydryl-l-piperazinyl)ethyl-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridin-3.5-dicarboxylat ist.
14. Dihydropyridin-Derivat nach Anspruch 1, das 2-[4-(4,4'-Difluorobenzhydryl)-1-piperazinyl]ethyl- methyl-2,6-dimethyl-4-(3-nitrophenyl)-1.4-dihydropyridin-3,5-dicarboxylat ist.
15. Dihydropyridin-Derivat nach Anspruch 1, das 2-[4-(4,4'-Dimethylbenzhydryl)-1-piperazinyl]ethyl- methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridin-3,5-dicarboxylat ist.
16. Dihydropyridin-Derivat nach Anspruch 1, das 2-[4-(4,4'-Dichlorobenzhydryl)-1-piperazinyl]ethyl- methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridin-3,5-dicarboxylat ist.
17. Dihydropyridin-Derivat nach Anspruch 1, das 2-[4-(3-Chlorophenyl)-1-piperazinyl]ethyl-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridin-3,5-dicarboxylat ist.
18. Dihydropyridin-Derivat nach Anspruch 1, das 2-(4-Benzhydryl-1-piperazinyl)ethyl-methyl-4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridin-3,5-dicarboxylat ist.
19. Pharmazeutische Zusammensetzung, umfassend als Wirkstoff eine wirksame Menge eines Dihydropyridin-Derivats oder eines Salzes desselben nach einem der Ansprüche 1 bis 18 und ein pharmazeutisch annehmbares Trägermaterial oder Verdünnungsmittel dafür.
20. Verfahren zur Herstellung eines Dihydropyridin-Derivats der Formel (I)
Figure imgb0174
(in der R1, R2 und R3 gleich oder verschieden sind und jeweils C1-6-Alkyl, C3-6-Cycloalkyl-C1-6-alkyl, C3-6-Cycloalkyl oder C3-7-Alkoxyalkyl sind; R4 und R5 gleich oder verschieden sind und jeweils Wasserstoff, Halogen, Nitro, Trifluoromethyl, C1-6-Alkyl, C3-6-Cycloalkyl-C1-6-alkyl, C3-6-Cycloalkyl, C1-3-Alkoxy, Cyano, C2-4-Alkoxycarbonyl oder C1-3-Alkylthio sind; R6 Wasserstoff, C1-6-Alkyl, C3-6-Cycloalkyl-C1-6-alkyl, C3-6-Cycloalkyl, Phenyl-C1-3-alkyl, Phenyl oder Naphthyl, das die gleichen oder unterschiedliche Substituenten R4 und R5 in wahlweisen Positionen haben kann, oder Pyridyl ist; X Sauerstoff, Schwefel, Vinylen, Azomethin oder eine Gruppe der Formel
Figure imgb0175
 A C2-4-Alkylen ist; Ar Phenyl oder Naphthyl oder ein Pyridyl ist; m eine ganze Zahl von 1 bis 3 ist; n eine ganze Zahl von 0 bis 2 ist) oder eines pharmazeutisch annehmbaren Säureadditionssalzes desselben, worin irgendeines der Fragmente, die das Derivat zu bilden vermögen, der Reaktion der Dehydrierung und Cyclisierung mit dem verbleibenden Fragment oder den verbleibenden Fragmenten nach einem der folgenden Herstellungsverfahren (A) bis (F) unterworfen wird:
Figure imgb0176
Figure imgb0177
Figure imgb0178
Figure imgb0179
Figure imgb0180
Figure imgb0181
wobei in den vorstehenden Formeln (II) bis (VIII) die verschiedenen Symbole die gleichen Bedeutungen haben, wie sie in Verbindung mit der Formel (I) angegeben sind, und gegebenenfalls das Dihydropyridin-Derivat (I) durch Reaktion mit einer geeigneten Säure in an sich bekannter Weise in ein pharmazeutisch annehmbares Säureadditionssalz überführt wird.
21. Dihydropyridin-Derivate und deren pharmazeutisch annehmbare Salze zur Verwendung bei der Herstellung von Medikamenten als prophylaktische und/oder therapeutische Arzneimittel für Herz-Kreislauf-Erkrankungen, wobei die Dihydropyridin-Derivate die Formel (I)
Figure imgb0182
haben, (in der R1, R2 und R3 gleich oder verschieden sind und jeweils C1-6-Alkyl, C3-6-Cycloalkyl-C,_s-alkyl, C3-6-Cycloalkyl oder C3-7-Alkoxyalkyl sind; R4 und R5 gleich oder verschieden sind und jeweils Wasserstoff, Halogen, Nitro, Trifluoromethyl, C1-6-Alkyl, C3-6-Cycloalkyl-C1-8-alkyl, C3-6-Cycloalkyl, C1-3-Alkoxy, Cyano, C2-4-Alkoxycarbonyl oder C1-3-Alkylthio sind; R6 Wasserstoff, C1-6-Alkyl, C3-6-Cycloalkyl-C1-6-alkyl, C3-6-Cycloalkyl, Phenyl-C1-3-alkyl, Phenyl oder Naphthyl, das die gleichen oder unterschiedliche Substituenten R4 und R5 in wahlweisen Positionen haben kann, oder Pyridyl ist; X Sauerstoff, Schwefel, Vinylen, Azomethin oder eine Gruppe der Formel
Figure imgb0183
A C2-4-Alkylen ist; Ar Phenyl oder Naphthyl oder ein Pyridyl ist; m eine ganze Zahl von 1 bis 3 ist; n eine ganze Zahl von 0 bis 2 ist) und die Salze pharmazeutisch annehmbare Säureadditionssalze der Verbindungen (I) sind.
EP83302139A 1982-05-10 1983-04-15 Dihydropyridinderivate, deren Herstellung und Verwendung Expired EP0094159B1 (de)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AT83302139T ATE50987T1 (de) 1982-05-10 1983-04-15 Dihydropyridinderivate, deren herstellung und verwendung.
MYPI87002229A MY102082A (en) 1982-05-10 1987-09-29 Dihydropyridine derivatives, their production and use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
WOPCT/JP82/00159 1982-05-10
PCT/JP1982/000159 WO1983004023A1 (en) 1982-05-10 1982-05-10 Dihydropyridine derivatives
PCT/JP1983/000008 WO1984002702A1 (en) 1983-01-11 1983-01-11 Dihydropyridine derivatives
WOPCT/JP83/00008 1983-01-11

Publications (2)

Publication Number Publication Date
EP0094159A1 EP0094159A1 (de) 1983-11-16
EP0094159B1 true EP0094159B1 (de) 1990-03-14

Family

ID=26422991

Family Applications (1)

Application Number Title Priority Date Filing Date
EP83302139A Expired EP0094159B1 (de) 1982-05-10 1983-04-15 Dihydropyridinderivate, deren Herstellung und Verwendung

Country Status (16)

Country Link
US (1) US4892875A (de)
EP (1) EP0094159B1 (de)
KR (1) KR880002357B1 (de)
AT (1) ATE50987T1 (de)
AU (1) AU556150B2 (de)
CA (1) CA1333487C (de)
DK (1) DK160984C (de)
ES (3) ES8607966A1 (de)
FI (1) FI79700C (de)
GR (1) GR78252B (de)
HK (1) HK3293A (de)
IE (1) IE56057B1 (de)
IL (1) IL68494A (de)
MY (1) MY102082A (de)
NO (1) NO159593C (de)
PT (1) PT76653B (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011023954A2 (en) 2009-08-27 2011-03-03 Cipla Limited Polymorphic forms of manidipine
US8501777B2 (en) 2005-10-13 2013-08-06 Nsab, Filial Af Neurosearch Sweden Ab, Sverige 3,5-disubstituted phenyl-piperidines as modulators of dopamine neurotransmission

Families Citing this family (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0097821B1 (de) * 1982-06-03 1988-07-13 Pierrel S.p.A. Dihydropyridine mit Calciumantagonistischer Wirkung, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
WO1985000169A1 (en) * 1983-06-21 1985-01-17 Sandoz Ag 1,4-dihydropyridine derivatives, production thereof and pharmaceutical preparations containing them
US5137889A (en) * 1983-12-02 1992-08-11 Otsuka Pharmaceutical Co., Ltd. Dihydropyridine derivatives and process for preparing the same
JPS60120861A (ja) * 1983-12-02 1985-06-28 Otsuka Pharmaceut Co Ltd ジヒドロピリジン誘導体
GB8403866D0 (en) * 1984-02-14 1984-03-21 Recordati Chem Pharm Diphenylalkylaminoalkyl esters
IE57810B1 (en) * 1984-03-27 1993-04-21 Delagrange Lab 1,4-dihydropyridine derivatives,their preparation and their use
US4895846A (en) * 1984-04-11 1990-01-23 Bristol-Myers Company Pharmaceutically useful dihydropyridinyldicarboxylate amides and esters incorporating arylpiperazinylalkyl moieties
US4755512A (en) * 1984-04-11 1988-07-05 Bristol-Myers Company Pharmaceutically useful dihydropyridinyldicarboxylate amides and esters incorporating arylpiperazinylalkyl moities
IL76366A (en) * 1984-09-14 1989-07-31 Ciba Geigy Ag 2,6-dialkyl-4-aryl-3,5-diacyl-1,4-dihydropyridine derivatives,processes for their manufacture and pharmaceutical preparations containing them
IT1196272B (it) * 1984-09-28 1988-11-16 Poli Ind Chimica Spa Derivati di 1,4-diidropiridina e composizioni farmaceutiche che li contengono
EP0176956B1 (de) * 1984-09-28 1994-06-15 Byk Gulden Lomberg Chemische Fabrik GmbH Neue Diarylverbindungen
HUT39179A (en) * 1984-12-10 1986-08-28 Sandoz Ag Process for production of derivatives of 1,4-dihydro-piridin
EP0205511A1 (de) * 1984-12-21 1986-12-30 Byk Gulden Lomberg Chemische Fabrik GmbH Neue piperazinderivate
IT1191845B (it) * 1986-01-20 1988-03-23 Dompe Farmaceutici Spa Alchiloli derivati farmacologicamente attivi
DK114587A (da) * 1986-03-12 1987-09-13 Byk Gulden Lomberg Chem Fab Monocycliske esterderivater
US4814455A (en) * 1986-04-16 1989-03-21 Bristol-Myers Company Dihydro-3,5-dicarboxylates
US4868181A (en) * 1986-08-04 1989-09-19 E. I. Du Pont De Nemours And Company 1,4-dihydropyridine derivatives with calcium agonist and alpha1 -antagonist activity
JPH0725750B2 (ja) * 1987-12-18 1995-03-22 富士レビオ株式会社 １，４‐ジヒドロピリジン誘導体
DE68929177T2 (de) * 1988-05-19 2000-10-19 Yoshitomi Pharmaceutical Verwendung von Dihydropyridinen zur Vorbeugung und Behandlung cerebraler Durchblutungsstörungen
US5286869A (en) * 1988-12-15 1994-02-15 Fujirebio Kabushiki Kaisha 1,4-dihydropyridine derivatives
JP2838282B2 (ja) * 1988-12-29 1998-12-16 吉富製薬株式会社 血管攣縮治療剤
USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
SE9904723D0 (sv) 1999-12-22 1999-12-22 Carlsson A Research Ab New modulators of dopamine neurotransmission II
SE9904724D0 (sv) 1999-12-22 1999-12-22 Carlsson A Research Ab New modulators of dopamine neurotransmission I
CN100450483C (zh) * 2000-04-11 2009-01-14 三共株式会社 含有钙阻滞剂的稳定药物组合物
EP1314425A4 (de) * 2000-08-30 2004-06-02 Sankyo Co Medizinische zusammenstellung zur prophylaxe und behandlung von herzversagen
CN1681495B (zh) 2002-08-19 2010-05-12 辉瑞产品公司 用于治疗过度增生性疾病的组合物
US20050037063A1 (en) * 2003-07-21 2005-02-17 Bolton Anthony E. Combined therapies
US7851629B2 (en) 2004-06-08 2010-12-14 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission
EP1768958B1 (de) * 2004-06-08 2009-11-18 NSAB, Filial af NeuroSearch Sweden AB, Sverige Neue disubstituierte phenylpiperidine als modulatoren der dopamin- und serotoninneurotransmission
SE0401465D0 (sv) 2004-06-08 2004-06-08 Carlsson A Research Ab New substituted piperdines as modulators of dopamine neurotransmission
DE602005021641D1 (de) * 2004-06-08 2010-07-15 Nsab, Filial Af Neurosearch Sweden Ab Neue disubstituierte phenylpiperidine und piperazine als modulatoren der dopamin-neurotransmission
BRPI0513866A (pt) * 2004-07-26 2008-05-20 Cotherix Inc composição, micropartìculas, método para o tratamento da hipertensão pulmonar, e dispositivo de inalação
CN101056854B (zh) 2004-10-13 2013-06-05 Nsab神经研究瑞典公司分公司 合成4-(3-甲磺酰基苯基)-1-n-丙基-哌啶的方法
US7741317B2 (en) 2005-10-21 2010-06-22 Bristol-Myers Squibb Company LXR modulators
US7893050B2 (en) * 2005-10-26 2011-02-22 Asahi Kasei Pharma Corporation Fasudil in combination therapies for the treatment of pulmonary arterial hypertension
EP2351569B1 (de) 2005-10-26 2012-08-22 Asahi Kasei Pharma Corporation Kombinationstherapie mit Fasudil zur Behandlung von pulmonaler Hypertonie
US7888376B2 (en) 2005-11-23 2011-02-15 Bristol-Myers Squibb Company Heterocyclic CETP inhibitors
TW200736245A (en) * 2005-11-29 2007-10-01 Sankyo Co Acid addition salts of optically active dihydropyridine derivatives
TW200806648A (en) * 2005-11-29 2008-02-01 Sankyo Co Acid addition salts of dihydropyridine derivatives
US7919506B2 (en) 2006-03-10 2011-04-05 Pfizer Inc. Dibenzyl amine compounds and derivatives
CN101663262B (zh) 2006-12-01 2014-03-26 百时美施贵宝公司 用于治疗动脉粥样硬化和心血管疾病的作为cetp抑制剂的n-(3-苄基)-2,2-(二苯基)-丙-1胺衍生物
CN101215258A (zh) * 2008-01-21 2008-07-09 中国药科大学 二氢吡啶类钙拮抗剂化合物及其制备方法与医药用途
CN101575313B (zh) * 2009-01-20 2012-04-18 许昌恒生制药有限公司 无柱层析法分离合成盐酸马尼地平生产工艺
US8883844B2 (en) 2010-09-24 2014-11-11 Nitrogenix Inc. Nitric oxide releasing amino acid ester for treatment of pulmonary hypertension and other respiratory conditions
UY34503A (es) 2011-12-08 2013-07-31 Ivax Int Gmbh ?sal de bromhidrato de pridopidina?
JP6177875B2 (ja) 2012-04-04 2017-08-09 テバ・ファーマシューティカルズ・インターナショナル・ゲーエムベーハーＴｅｖａ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｔｅｒｎａｔｉｏｎａｌ ＧｍｂＨ 併用療法のための医薬組成物
CN102875451B (zh) * 2012-04-05 2014-12-03 常州制药厂有限公司 一种盐酸马尼地平合成工艺的改进方法
WO2014170786A1 (en) 2013-04-17 2014-10-23 Pfizer Inc. N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases
CN103351362A (zh) * 2013-06-17 2013-10-16 张家港威胜生物医药有限公司 一种马尼地平中间体2-(4-二苯甲基哌嗪)乙基乙酰乙酸酯的制备方法
CN103467364B (zh) * 2013-06-21 2015-07-15 四川海思科制药有限公司 一种盐酸马尼地平化合物
WO2016055901A1 (en) 2014-10-08 2016-04-14 Pfizer Inc. Substituted amide compounds
CN106380442A (zh) * 2016-09-07 2017-02-08 张家港威胜生物医药有限公司 一种钙离子通道拮抗剂马尼地平的制备方法
CN106518806A (zh) * 2016-09-07 2017-03-22 张家港威胜生物医药有限公司 一种马尼地平中间体2‑(4‑二苯甲基哌嗪)乙基乙酰乙酸酯的制备方法
CN113574055A (zh) 2019-01-18 2021-10-29 阿斯利康(瑞典)有限公司 Pcsk9抑制剂及其使用方法

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3472853A (en) * 1967-05-29 1969-10-14 Sterling Drug Inc 1-((pyrido(2,1-c)-s-triazolyl)-lower-alkyl)-4-substituted- piperazines
DE2218644C3 (de) * 1972-04-18 1982-08-19 Bayer Ag, 5090 Leverkusen Basische Ester von 1,4-Dihydropyridinen, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimittel
DE2239815C2 (de) * 1972-08-12 1983-02-10 Bayer Ag, 5090 Leverkusen 2-Alkylamino-dihydropyridine, Verfahren zu ihrer Herstellung sowie diese enthaltende Arzneimittel
GB1455502A (en) * 1973-02-20 1976-11-10 Yamanouchi Pharma Co Ltd 1,4-dihydropyridine derivatives
JPS55301A (en) * 1978-02-14 1980-01-05 Yamanouchi Pharmaceut Co Ltd 1,4-dihydropyridine-3,5-dicarboxylic ester derivative and its preparation
DE2949464A1 (de) * 1978-12-18 1980-06-26 Sandoz Ag Benzoxadiazole und benzothiadiazole, ihre herstellung und verwendung
DE3022030A1 (de) * 1980-06-12 1981-12-17 Bayer Ag, 5090 Leverkusen 4-thiazol- bzw. 4-imidazol-substituierte, 1,4-dihydropyridine, verfahren zu deren herstellung sowie diese enthaltende arzneimittel
DE3042769A1 (de) * 1980-11-13 1982-06-09 Bayer Ag, 5090 Leverkusen C-3 verknuepfte 1,4-dihydropyridine, ihre verwendung in arzneimitteln und verfahren zu ihrer herstellung
CS228917B2 (en) * 1981-03-14 1984-05-14 Pfizer Method of preparing substituted derivatives of 1,4-dihydropyridine
JPS57175166A (en) * 1981-04-23 1982-10-28 Banyu Pharmaceut Co Ltd Carbamoyloxyalkyl-1,4-dihydropyridine derivative and its preparation
DE3269219D1 (en) * 1981-11-17 1986-03-27 Fisons Plc Dihydropyridines, methods for their production and their formulation and use as pharmaceuticals

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8501777B2 (en) 2005-10-13 2013-08-06 Nsab, Filial Af Neurosearch Sweden Ab, Sverige 3,5-disubstituted phenyl-piperidines as modulators of dopamine neurotransmission
WO2011023954A2 (en) 2009-08-27 2011-03-03 Cipla Limited Polymorphic forms of manidipine
US9018376B2 (en) 2009-08-27 2015-04-28 Cipla Limited Polymorphic forms of manidipine

Also Published As

Publication number Publication date
DK203083A (da) 1983-11-11
DK160984B (da) 1991-05-13
MY102082A (en) 1992-03-31
HK3293A (en) 1993-01-21
AU1415583A (en) 1983-11-17
ES541668A0 (es) 1985-12-01
DK203083D0 (da) 1983-05-06
IE830897L (en) 1983-11-10
NO159593C (no) 1989-01-18
ATE50987T1 (de) 1990-03-15
FI831604L (fi) 1983-11-11
NO159593B (no) 1988-10-10
DK160984C (da) 1991-11-11
US4892875A (en) 1990-01-09
AU556150B2 (en) 1986-10-23
PT76653A (en) 1983-06-01
EP0094159A1 (de) 1983-11-16
IE56057B1 (en) 1991-04-10
ES8607966A1 (es) 1986-01-16
FI79700C (fi) 1990-02-12
PT76653B (en) 1986-01-27
ES522199A0 (es) 1986-01-16
IL68494A (en) 1988-01-31
FI79700B (fi) 1989-10-31
ES8602661A1 (es) 1985-12-01
ES8701171A1 (es) 1986-11-16
ES547275A0 (es) 1986-11-16
NO831613L (no) 1983-11-11
CA1333487C (en) 1994-12-13
KR880002357B1 (ko) 1988-10-29
KR840004741A (ko) 1984-10-24
IL68494A0 (en) 1983-07-31
GR78252B (de) 1984-09-26
FI831604A0 (fi) 1983-05-09

Similar Documents

Publication Publication Date Title
EP0094159B1 (de) Dihydropyridinderivate, deren Herstellung und Verwendung
US4999362A (en) 2-thiomethyl-substituted-1,4-dihydropyridines, method for their preparation and pharmaceutical compositions containing them
US4220649A (en) 1,4-Dihydropyridine-3,5-dicarboxylic acid ester derivatives
EP0176956B1 (de) Neue Diarylverbindungen
DE2752820A1 (de) Neue nitrosubstituierte 1,4-dihydropyridine, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
KR920005742B1 (ko) 약제학상 유용한 디하이드로피리디닐디카르복실레이트 아마이드 및 에스테르의 제조방법
EP0097821B1 (de) Dihydropyridine mit Calciumantagonistischer Wirkung, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
CZ281597B6 (cs) Enantiomery 1,4-dihydropyridinu, způsob jejich přípravy a farmaceutické prostředky z nich připravené
EP0138505A2 (de) Dihydropyridin-Derivate, ihre Herstellung und Verwendung
KR960009427B1 (ko) 1,4-디히드로피리딘 유도체, 그의 약학적 조성물 및 그 제조방법
US4895846A (en) Pharmaceutically useful dihydropyridinyldicarboxylate amides and esters incorporating arylpiperazinylalkyl moieties
US4500527A (en) Antihypertensive 4[(3-alkylamino-2-hydroxypropyl)-oxyiminomethyl phenyl]-1,4-dihydropyridines
JPS62281860A (ja) アルキレンアミノアルキレン　ヘテロ原子基を有するジヒドロ−３，５−ジカルボキシレ−ト
JP2640245B2 (ja) １，４−ジヒドロピリジン誘導体
EP0212340A1 (de) 2-(Heteroalkyl)-1,4-dihydropyridine, Verfahren zu deren Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
JPS6352031B2 (de)
JPS6330304B2 (de)
EP0220917B1 (de) Pharmazeutische 1,4-Dihydropyridinderivate, ihre Salze und Herstellung
JP2664941B2 (ja) １，４―ジヒドロピリジン化合物
JPS5976083A (ja) ジヒドロピリジン類
US4105781A (en) Chromone compounds and preparation thereof
US4049664A (en) Chromone compounds
HU190900B (en) Process for preparing dihydro-pyridine derivatives
US4302591A (en) Antihypertensive amines
JPS6321674B2 (de)

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

17P Request for examination filed

Effective date: 19840327

17Q First examination report despatched

Effective date: 19860610

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: TAKEDA CHEMICAL INDUSTRIES, LTD.

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

REF Corresponds to:

Ref document number: 50987

Country of ref document: AT

Date of ref document: 19900315

Kind code of ref document: T

ITF It: translation for a ep patent filed

Owner name: JACOBACCI & PERANI S.P.A.

ET Fr: translation filed
REF Corresponds to:

Ref document number: 3381313

Country of ref document: DE

Date of ref document: 19900419

REG Reference to a national code

Ref country code: AT

Ref legal event code: UEP

Ref document number: 50987

Country of ref document: AT

Kind code of ref document: T

R20 Corrections of a patent specification

Effective date: 19900709

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
ITTA It: last paid annual fee
EPTA Lu: last paid annual fee
EAL Se: european patent in force in sweden

Ref document number: 83302139.7

REG Reference to a national code

Ref country code: GB

Ref legal event code: IF02

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20020405

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20020410

Year of fee payment: 20

Ref country code: GB

Payment date: 20020410

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20020411

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20020412

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20020416

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20020424

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20020426

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20020619

Year of fee payment: 20

REG Reference to a national code

Ref country code: FR

Ref legal event code: CP

Free format text: PRODUCT NAME: MANIDIPINE HYDROCHLORIDE; NAT. REGISTRATION NO/DATE: NL 27 096 20020722; FIRST REGISTRATION: IT - AIC N 721/1995 19951117

Spc suppl protection certif: 02C0031

Filing date: 20020902

REG Reference to a national code

Ref country code: FR

Ref legal event code: CR

Free format text: FRCR 02C0031, 20020902

REG Reference to a national code

Ref country code: FR

Ref legal event code: CP

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20030414

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20030414

Ref country code: LI

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20030414

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20030415

Ref country code: AT

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20030415

Ref country code: NL

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20030415

BE20 Be: patent expired

Owner name: *TAKEDA CHEMICAL INDUSTRIES LTD

Effective date: 20030415

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

EUG Se: european patent has lapsed
REG Reference to a national code

Ref country code: AT

Ref legal event code: EELA

Ref document number: 50987

Country of ref document: AT

Kind code of ref document: T

REG Reference to a national code

Ref country code: FR

Ref legal event code: CY

Free format text: 2002C0031, 20020902, EXPIRES: 20080414

Spc suppl protection certif: 2002C0031

Filing date: 20020902

REG Reference to a national code

Ref country code: AT

Ref legal event code: ESZA

Free format text: PRODUCT NAME: MANIDIPIN UND PHARMAZEUTISCH VERTR?GLICHE SALZE DAVON

Spc suppl protection certif: SZ 16/2003

Filing date: 20030410

REG Reference to a national code

Ref country code: AT

Ref legal event code: EEZF

Spc suppl protection certif: SZ 16/2003

Filing date: 20030410

Extension date: 20080415

Effective date: 20060224

REG Reference to a national code

Ref country code: FR

Ref legal event code: CD

Spc suppl protection certif: 2002C0031